Receptor protein kinases regulate key signal transduction cascades that control or are involved in the control of a plethora of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, cell adhesion, stress response, short-range contact-mediated axonal guidance, transcription regulation, aberrant mitogenesis, angiogenesis, abnormal endothelial cell-cell or cell-matrix interactions during vascular development, inflammation, lymphohematopoietic stem cell activity, protective immunity against specific bacteria, allergic asthma, aberrant tissue-specific responses to the activation of the JNK signal transduction pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse modification at the neuromuscular synapse, immunological mediation of disease, and calcium regulation.
Exemplary disease states associated with aberrant regulation of protein kinases include, for example without limitation, acrocephalo-syndactyly type I, acute myeloid leukemia, AIDS-induced non-Hodgkin's lymphoma, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, bacterial infection, bladder cancer, cancer of the breast, cancer of the central nervous system, cancer of the colon, cancer of the endometrium, cancer of the fallopian tube, cancer of the gastrointestinal tract, cancer of the ovary, heart failure, chronic myeloid leukemia, colon carcinoma, colorectal cancer, chronic obstructive pulmonary disease (COPD), Crouzon Syndrome, diabetes, diabetic nephropathy, emphysema, endometriosis, epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor (GIST), glomerulonephritis, Graves' disease, head injury, hepatocellular carcinoma, Hirschsprung's disease, human gliomas, immunodeficiency diseases, inflammatory disorders, ischemic stroke, Jackson-Weiss syndrome, leiomyosarcoma, leukemias, lupus nephritis, malignant melanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors, melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine, multiple sclerosis, myeloproliferative disorders, nephritis, neurodegenerative diseases, neurotraumatic diseases, lung cancer, non small cell lung cancer, organ transplant rejection, osteoporosis, pain, Parkinson's disease, Pfeiffer Syndrome, polycystic kidney disease, primary lymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoid arthritis, dermal and tissue scarring, selective T-cell defect (STD), severe combined immunodeficiency (SCID), small cell lung cancer, spinal cord injury, squamous cell carcinoma, systemic lupus erythematosis, testicular cancer, thrombotic microangiopathy syndromes, Wegener's granulomatosis, X-linked agammaglobulinemia, viral infection, diabetic retinopathy, alopecia, erectile dysfunction, macular degeneration, chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), neurofibromatosis, and tuberous sclerosis.
The identification of activating BRAF mutations (primarily missense substitutions for Valine-600 or BRAFV600 in cancer supports a functionally important role for BRAF in the pathogenesis of these malignancies (Davies, H. et al. Nature 417, 949-954 (2002)). Specific BRAF inhibitors including vemurafenib and dabrafenib have demonstrated both objective tumor response and, in the case of vemurafenib, overall survival benefit in mutant BRAFV600 driven melanoma (Flaherty, K. T. et al. N Engl J Med 363, 809-819 (2010); Chapman, P. B. et al. N Engl J Med 364, 2507-2516 (2011); Sosman, J. A. et al. N Engl J Med 366, 707-714 (2012); Hauschild, A. et al. Lancet 380, 358-365 (2012); Bollag, G. et al. Nature 467, 596-599 (2010); and Stellwagen, J. C. et al. Bioorg Med Chem Lett 21, 4436-4440 (2011)). The clinical effectiveness of BRAF inhibitor-based therapy depends on complete abolition of the MAPK pathway output in tumors harboring BRAF mutations (Bollag, G. et al. Nature 467, 596-599 (2010)). However these compounds paradoxically activate the MAPK pathway in cells bearing oncogenic RAS or elevated upstream receptor signaling (Hatzivassiliou, G. et al. Nature 464, 431-435 (2010); Heidorn, S. J. et al. Cell 140, 209-221 (2010); and Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. Nature 464, 427-430 (2010)). This activation can lead to cellular proliferation and has been associated clinically with appearance of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas (KAs), sometimes within weeks of initiation of therapy (Hauschild, A. et al. Lancet 380, 358-365 (2012); Bollag, G. et al. Nature 467, 596-599 (2010); Huang, V., Hepper, D., Anadkat, M. & Cornelius, L. Arch Dermatol 148, 628-633 (2012); and Anforth, R. M. et al. Br J Dermatol 167, 1153-1160 (2012)). Accordingly, there is a need in the art for compounds and methods of use thereof for modulation of receptor protein kinases. The disclosure herein meets this and other needs.